CN1498216A - Noval crystal and solvate forms of ondansetron hydrochloride and process for their preparation - Google Patents
Noval crystal and solvate forms of ondansetron hydrochloride and process for their preparation Download PDFInfo
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- CN1498216A CN1498216A CNA018183859A CN01818385A CN1498216A CN 1498216 A CN1498216 A CN 1498216A CN A018183859 A CNA018183859 A CN A018183859A CN 01818385 A CN01818385 A CN 01818385A CN 1498216 A CN1498216 A CN 1498216A
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- Prior art keywords
- ondansetron hydrochloride
- type
- ondansetron
- hydrochloride
- anhydrous
- Prior art date
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- MKBLHFILKIKSQM-UHFFFAOYSA-N 9-methyl-3-[(2-methyl-1h-imidazol-3-ium-3-yl)methyl]-2,3-dihydro-1h-carbazol-4-one;chloride Chemical compound Cl.CC1=NC=CN1CC1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 MKBLHFILKIKSQM-UHFFFAOYSA-N 0.000 title claims abstract description 264
- 229960000770 ondansetron hydrochloride Drugs 0.000 title claims abstract description 246
- 238000000034 method Methods 0.000 title claims abstract description 91
- 230000008569 process Effects 0.000 title claims abstract description 8
- 239000013078 crystal Substances 0.000 title claims description 25
- 238000002360 preparation method Methods 0.000 title claims description 25
- 239000012453 solvate Substances 0.000 title abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 165
- 229960005343 ondansetron Drugs 0.000 claims description 105
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 claims description 74
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 58
- 239000003513 alkali Substances 0.000 claims description 51
- 239000000203 mixture Substances 0.000 claims description 43
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 42
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 33
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 33
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 31
- 229960004756 ethanol Drugs 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 30
- FELGMEQIXOGIFQ-UHFFFAOYSA-N Ondansetron Chemical compound CC1=NC=CN1CC1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-UHFFFAOYSA-N 0.000 claims description 28
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000002245 particle Substances 0.000 claims description 20
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- 239000000725 suspension Substances 0.000 claims description 18
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- 239000007788 liquid Substances 0.000 claims description 15
- 150000004683 dihydrates Chemical class 0.000 claims description 14
- 239000007789 gas Substances 0.000 claims description 13
- 238000009826 distribution Methods 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 10
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- 238000006703 hydration reaction Methods 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 9
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- 150000004682 monohydrates Chemical class 0.000 claims description 8
- 206010047700 Vomiting Diseases 0.000 claims description 6
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- 239000000155 melt Substances 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 2
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- 150000002576 ketones Chemical group 0.000 claims description 2
- 238000010907 mechanical stirring Methods 0.000 claims 2
- PQMWYJDJHJQZDE-UHFFFAOYSA-M Methantheline bromide Chemical compound [Br-].C1=CC=C2C(C(=O)OCC[N+](C)(CC)CC)C3=CC=CC=C3OC2=C1 PQMWYJDJHJQZDE-UHFFFAOYSA-M 0.000 claims 1
- 239000002131 composite material Substances 0.000 claims 1
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- 150000004677 hydrates Chemical class 0.000 abstract 1
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- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 19
- 238000003756 stirring Methods 0.000 description 16
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- KZMAWJRXKGLWGS-UHFFFAOYSA-N 2-chloro-n-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-n-(3-methoxypropyl)acetamide Chemical compound S1C(N(C(=O)CCl)CCCOC)=NC(C=2C=CC(OC)=CC=2)=C1 KZMAWJRXKGLWGS-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
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- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 206010025482 malaise Diseases 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
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- 230000000704 physical effect Effects 0.000 description 2
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- 238000001959 radiotherapy Methods 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 238000000935 solvent evaporation Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- XINQFOMFQFGGCQ-UHFFFAOYSA-L (2-dodecoxy-2-oxoethyl)-[6-[(2-dodecoxy-2-oxoethyl)-dimethylazaniumyl]hexyl]-dimethylazanium;dichloride Chemical compound [Cl-].[Cl-].CCCCCCCCCCCCOC(=O)C[N+](C)(C)CCCCCC[N+](C)(C)CC(=O)OCCCCCCCCCCCC XINQFOMFQFGGCQ-UHFFFAOYSA-L 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- XZXYQEHISUMZAT-UHFFFAOYSA-N 2-[(2-hydroxy-5-methylphenyl)methyl]-4-methylphenol Chemical compound CC1=CC=C(O)C(CC=2C(=CC=C(C)C=2)O)=C1 XZXYQEHISUMZAT-UHFFFAOYSA-N 0.000 description 1
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
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- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229940107816 ammonium iodide Drugs 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
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- 238000007796 conventional method Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- NSNHWTBQMQIDCF-UHFFFAOYSA-N dihydrate;hydrochloride Chemical compound O.O.Cl NSNHWTBQMQIDCF-UHFFFAOYSA-N 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
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- 238000005265 energy consumption Methods 0.000 description 1
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- 239000011521 glass Substances 0.000 description 1
- 229940015043 glyoxal Drugs 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 231100000652 hormesis Toxicity 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
Abstract
The present invention provides novel ondansetron hydrochloride crystalline polymorphic forms and solvates. Processes for making and interconverting the polymorphic forms are also provided. Further provided are pharmaceutical compositions and therapeutic methods using the novel polymorphic forms and hydrates.
Description
The cross reference of related application
The application requires the right of priority of following provisional application: the 60/244th, No. 283 provisional application that on October 30th, 2000 submitted to; The 60/253rd, No. 819 provisional application that on November 29th, 2000 submitted to; With the 60/265th, No. 539 provisional application of submitting to January 31 calendar year 2001.
Invention field
The method that the application relates to new ondansetron hydrochloride polymorphic form and hydrate and prepares ondansetron hydrochloride polymorphic form and hydrate.
Background of invention
(±) 1,2,3 with following molecular structure, 9-tetrahydrochysene-9-methyl-3-[2-methyl isophthalic acid H-imidazoles-1-yl) methyl]-4H-carbazole-4-ketone
Be selectivity 5-HT
3Receptor antagonist.Its popular name is ondansetron (ondansetron).Ondansetron can alleviate feeling sick of patients undergoing chemotherapy.Grunberg, S.M.; Hesketh, P.J. " vomiting that the control chemotherapy causes " N.Engl.J.Med.1993,329,1790-96.Ondansetron can be used for preventing and some cancer chemotherapy, the relevant nauseating and/or vomiting of nausea and vomiting and operation back of radiotherapy.
The hydrochloride of ondansetron generally is safe for giving patient's oral administration, can not cause hormesis or other undesirable action.This hydrochloride is with Zofran
Trade(brand)name commercially available with tablet form and oral liquid form.The active ingredient of tablet is the dihydrate of ondansetron hydrochloride, and it comprises two bound water molecules in the lattice of ondansetron hydrochloride.
The present invention relates to the solid state physical properties of ondansetron hydrochloride.Can influence these character by the condition of control acquisition solid form hydrochloride.Solid state physical properties comprises for example flowability of milled solid.Flowability affects is handled the easy degree of material during being processed into medicine.When the particle of powder compounds can not easily flow each other, formulation specialist must be considered this fact when exploitation tablet or capsule preparations, may make to use glidant for example colloidal silica, talcum powder, starch or calcium phosphate.
Another important solid character of medical compounds is its dissolution rate in aqueous fluid.The dissolution rate of active ingredient in patient's gastric juice can have the treatment consequence, because its speed of can arrive patient's blood flow for Orally administered active ingredient has applied the upper limit.Dissolution rate still is the factor that obtain syrup agent, elixir and other liquid medicine will be considered.The compound of solid-state form can also influence its compression habit and storage stability.
The molecular conformation and the direction that limit in the polymorphous structure cell of material can influence these important physical features.Llacer and co-worker thereof have proposed such hypothesis, why the ondansetron free alkali sample that makes by different way has different spectral signatures is because about 1,2,3, the methylene bridge between 9-tetrahydro carbazole-4-ketone ring and the imidazole ring has two kinds of not isomorphism types.Llacer，J.M.；Gallardo，V.；Parera，A.Ruiz，M.A.Intern.J.Pharm.，177，1999，221-229。
A kind of crystalline polymorph of compound can show the hot habit different with amorphous substance or another polymorphic form.Hot habit is by such as the such technical measurement of capillary melting point, thermogravimetric analysis (TGA) and dsc (DSC) in the laboratory, and can be used for some polymorphic form and the difference of other polymorphic form are come.Specific polymorphic form can also cause different spectral qualities, and these spectral qualities can pass through powder X-ray-radiocrystallgraphy, solid-state
13C NMR spectrophotometry and infrared spectrophotometry detect.The multiple technology that can produce the different crystal forms of compound is arranged.The example comprises crystallization, crystal boiling, distillation and thermal treatment.
U.S. patent 4,695, and 578 embodiment 1a discloses and passed through with 2,3,4,9-tetrahydrochysene-N, and N, N, 9-tetramethyl--4-oxo-1H-carbazole-3-first ammonium iodide prepare ondansetron with the glyoxal ethyline alkylation.In this embodiment, ondansetron is to come out with the isolated in form of its hydrochloride by following aftertreatment: reaction product is suspended in the mixture of dehydrated alcohol and HCl ethanolic soln, warm this suspension filters to remove impurity, is settled out hydrochloride with anhydrous diethyl ether.
In the embodiment 10 of U.S. patent 4,695,578, by the ondansetron free alkali is dissolved in the mixture of Virahol and water, and handles with concentrated hydrochloric acid the ondansetron free alkali is changed into hydrochloride dihydrate.Behind high temperature filtration, ondansetron is separated out from solution it by adding Virahol again and cooling off.By with its recrystallization from 6: 10 mixtures of water and Virahol, obtained to be the dihydrate of white crystalline solid.The ondansetron hydrochloride dihydrate that obtains according to the embodiment 10 of U.S. patent 4,695,578 is named as the A type in this patent.The Powder samples of A type has produced the powder x-ray diffraction pattern substantially the same with pattern shown in the accompanying drawing 1.
U.S. patent 5,344, and 658 have described and have ondansetron that specified particle diameter distributes and the such application of ondansetron in pharmaceutical composition.Ondansetron hydrochloride dihydrate for obtaining by crystallization from solvent has reduced its particle diameter by following method: for example desolvation is exposed to desolvated crystal under the moistening atmosphere then by heating with its desolvation.According to wherein describing, reduce the crystal set that method obtains by this particle diameter and only forms less than 250 microns crystal, and contain 80% or more crystal less than 63 microns by particle diameter.Crystallographic dimension is measured by the air spray screen analysis.
According to U.S. patent 5,344,658, also provide ondansetron hydrochloride dehydrate with size distribution identical with rehydrated ondansetron hydrochloride as this invention part.Because only described in the U.S. patent 5,344,658 a kind of with the ondansetron hydrochloride dehydration method, so dehydrate obviously is to reduce intermediate compound rehydrated in the method at particle diameter.
With U.S. patent 4,695,578 and 5,344,658 introduce the present invention with for referencial use.
The novel polymorphic thing of finding pharmaceutically acceptable compound provides new chance to the performance characteristic of improving medicine.Its enlarged the preparation scholar for design example as having target and discharge or the pharmaceutical dosage form of other desired characteristic and the number of the material that can utilize.6 kinds of new ondansetron hydrochloride polymorphic form and solvates have been had been found that now.
Summary of the invention
The purpose of this invention is to provide new ondansetron hydrochloride form and preparation method thereof.
Therefore, the invention provides a kind of new ondansetron hydrochloride monohydrate, described monohydrate can be made by ondansetron hydrochloride dihydrate or ondansetron free alkali according to the inventive method.This monohydrate is called A type hydrochloride, and this is because its X-ray spectrum feature and known ondansetron hydrochloride dihydrate are similar.
The present invention also provides the new anhydrous ondansetron hydrochloride form of called after Type B.Type B has favourable grain diameter characteristic, and only moisture absorption slightly.Type B can be made by A type ondansetron hydrochloride and ondansetron free alkali.
The invention also discloses ondansetron hydrochloride form of called after C type, D type and H type and preparation method thereof.
The present invention also provides the Virahol thing of ondansetron hydrochloride and methylate and preparation method thereof.
Ondansetron hydrochloride anhydrous form of the present invention and hydrate are applicable to that preparation is used for preventing the pharmaceutical composition of feeling sick that feel sick in the back and chemotherapeutic period is caused of performing the operation.
The accompanying drawing summary
Accompanying drawing 1 is the powder x-ray diffraction pattern of A type ondansetron hydrochloride.
Accompanying drawing 2 is powder x-ray diffraction patterns of Type B ondansetron hydrochloride.
Accompanying drawing 3 is powder x-ray diffraction patterns of C type ondansetron hydrochloride.
Accompanying drawing 4 is powder x-ray diffraction patterns of E type ondansetron hydrochloride.
Accompanying drawing 5 is thermogravimetric analysis figure of E type ondansetron hydrochloride.
Accompanying drawing 6 is powder x-ray diffraction patterns of H type ondansetron hydrochloride.
Accompanying drawing 7 is powder x-ray diffraction patterns of I type ondansetron hydrochloride.
Accompanying drawing 8 is thermogravimetric analysis figure of I type ondansetron hydrochloride.
Detailed Description Of The Invention
Ondansetron hydrochloride one hydrate
On the one hand, the invention provides ondansetron hydrochloride one hydrate. Find that this is one years old Hydrate has and the hydrochloric acid that obtains according to the method for U.S. patent 4,695,578 embodiment 10 The identical structure cell of monocalcium salt compound (called after A type in this patent). Obtained by a hydrate The X-ray diffraction pattern (with the unusual phase of the X-ray diffraction pattern that is obtained by A type dihydrate Join) in found that this hydrate has and/or keeps crystal form A (depending on its preparation method) Evidence. This is to show approximately identical strong evidence of crystal structure. A type Ondansetron hydrochloric acid Salt is characterised in that: the strong diffraction at 23.3 ± 0.2 ° of 2 θ angle, and at following 2 θ angles Other diffraction peak: 6.1,12.4,17.0,18.3,19.2,20.3,20.9,24.1,25.8, 28.1,30.3 ± 0.2 °. The X-of A type one hydrate sample as shown in Figure 1 is provided Ray diffraction pattern. Common by the isolated A type of the inventive method ondansetron hydrochloride Bigger dull and stereotyped shape crystal.
A type ondansetron hydrochloride can be with between a hydrate and the dihydrate level Middle hydration degree exists. A type ondansetron hydrochloride can be tied under condition disclosed by the invention Crystalline substance, and have different foreseeable moisture levels. Be present in any Ondansetron of the present invention The amount of the moisture in the hydrate forms can be passed through for example Karl Fisher method mensuration of conventional method.
With freshly prepd A type ondansetron hydrochloride sample be exposed to have control humidity for example 60% or the atmosphere of higher relative humidity under so that the moisture level in the crystal increases sharply Reach about 10.0% dihydrate moisture contents level. The moisture picked-up was sent out in several hours usually Give birth to, perhaps in the generation of spending the night at the most. The dehydration of A type Ondansetron dihydrate is to littler hydration shape The easiness of attitude, and more rudimentary hydrate rehydrated one-tenth dihydrate level under moistening atmosphere Ability to have confirmed to have at least in the ondansetron hydrochloride dihydrate crystallization water be unstable .
By with A type ondansetron hydrochloride dihydrate in the vacuum baking oven in 90 ℃ of dryings 12 Hour, A type Ondansetron one hydrate can dewater to moisture content be 1.3% or lower base Anhydrous state on the basis. A type Ondansetron with such low moisture content has also kept the A type The crystal structure of ondansetron hydrochloride, so its feature also is A type ondansetron hydrochloride The powder x-ray diffraction pattern. By being exposed to 50%-60% relative humidity. High dehydration A type ondansetron hydrochloride can be rehydrated, and change into the ondansetron hydrochloride dihydrate (10.0% moisture).
Prepare A type ondansetron hydrochloride one hydrate by A type ondansetron hydrochloride dihydrate
A type ondansetron hydrochloride monohydrate can be made by A type ondansetron hydrochloride dihydrate.Be suspended in the aqueous ethanol liquid medium dihydrate or pulp therein.Preferred liquid medium is about 50% ethanol/water-Yue 96% ethanol/water mixture.Between the hydration level of the A type that is obtained and the ratio of water in liquid medium, there is not direct dependency.Water in this scope and alcoholic acid mixture have produced such A type, the moisture content of its mensuration is consistent with 5.18% the ondansetron hydrochloride monohydrate moisture content of being calculated, and for example the embodiment 14 and 15 by more hereinafter can see this point.
Preferably with the suspension or the slurry reflux of A type dihydrate, with the partial dehydration that promotes in the mixture of these ethanol and water, to take place.By with this suspension cooling and filtration, A type monohydrate can be separated from liquid medium easily.
Further for example understand this method with embodiment 12-19.Embodiment 18 and 19 understands that for example monohydrate can also use the liquid medium of some non-water, particularly ethanol/Virahol and ethanol/toluene mixture to obtain.Yet shown in embodiment 20-25, such mixture causes that generally A type ondansetron hydrochloride is with the middle hydration status crystallization between monohydrate and dihydrate.Moisture content is that the ondansetron hydrochloride of 6-9%-between monohydrate (5.18%) and dihydrate (9.85%) is that method circulation ratio ground by embodiment 20-25 obtains.
Prepare A type ondansetron hydrochloride by ondansetron alkali
When forming ondansetron hydrochloride by free alkali, the currently known methods of preparation A type ondansetron hydrochloride is to use the mixture of water and Virahol and water/Virahol/acetate mixture as solvent.These solvent systemss cause that all the time ondansetron hydrochloride crystallizes out as dihydrate.
The invention provides the novel method for preparing A type ondansetron hydrochloride by the ondansetron free alkali.In this novel method, free alkali is suspended in the dehydrated alcohol, and handles with excessive a little anhydrous HCl.HCl can be used as gas and provides or be dissolved in organic solvent and for example provide in dehydrated alcohol, toluene, methyl ethyl ketone, Virahol or the ether.Preferably this suspension is heated to backflow to accelerate the free alkali dissolving and to change into hydrochloride.A type dihydrate be by with solution cooling causing crystallization, and filter and obtain easily to isolate solvent and any impurity.
Embodiment 1-11 further for example understands this method.
We have found that by using for example chloroform of optional and water blended chlorinated solvent, can obtain the ondansetron hydrochloride as monohydrate, embodiment 8-11 has done this further to illustrate.
The anhydrous ondansetron hydrochloride of Type B
The invention provides new ondansetron hydrochloride form that is called the anhydrous ondansetron hydrochloride of Type B and the method for preparing the anhydrous ondansetron hydrochloride of Type B.The anhydrous ondansetron hydrochloride of Type B can be made by A type ondansetron hydrochloride or ondansetron alkali.
The anhydrous ondansetron hydrochloride of Type B is characterised in that: the strong powder x-ray diffraction peak at 11.9 ± 0.2 ° of 2 θ angle, and at the powder x-ray diffraction peak at following 2 θ angles: 10.5,13.0,13.5,15.1,20.9,22.7,24.0,25.7 ± 0.2 °.The X-ray diffraction pattern of Type B sample as shown in Figure 2 is provided.In our hand, the anhydrous ondansetron hydrochloride of Type B is rendered as the fine powder of mainly being made up of little spicule and post.
When the relative humidity that is exposed to 60%, the anhydrous ondansetron hydrochloride of Type B of the present invention absorbs and is up to 2% moisture.The moisture that crystal absorbs does not resemble the water of hydration in the crystalline structure of hydrated form.Can for example there be water of hydration in the PXRD monitoring crystalline structure by conventional means.Use x-ray powder diffraction technique, do not have water of hydration by not existing A type ondansetron hydrochloride to indicate in the sample.Having the A type is by the indication of strong peak occurs at 12.3 ° of 2 θ angle in the X-ray diffraction pattern of sample.
The present invention also provides the preparation of little Type B ondansetron hydrochloride particulate, and described particulate advantage is to need not expensive and processing high energy consumption for example grinds in a large number or complicated dehydration and rehydrated processing realizes that required particle diameter reduces.Feature is that the size distribution with Type B ondansetron hydrochloride of little pin/rod shaped particles is such: maximum particle diameter is 200 microns, has the d (0.9) that is up to 140 microns usually, is up to 30 microns d (0.5), is up to 2 microns d (0.1).D (0.9) value preferably is up to 40 microns.
Prepare the anhydrous ondansetron hydrochloride of Type B by A type ondansetron hydrochloride
According to the inventive method, the anhydrous ondansetron hydrochloride of Type B can be made by A type ondansetron hydrochloride by following manner: use anhydrous C
1-C
4Alcoholic solvent for example ethanol, Virahol and 1-butanols or ketones solvent for example acetone and methyl ethyl ketone (" MEK ") are handled A type ondansetron hydrochloride.When the inventive method of preparation Type B anhydrous ondansetron hydrochloride is when room temperature is carried out, preferred solvent is acetone, methyl ethyl ketone, dehydrated alcohol or Virahol and alcoholic acid mixture (preferably also using dehydrated alcohol in this mixture).The used dehydrated alcohol of the application is meant and contains the ethanol that is no more than 0.5% water.Virahol and alcoholic acid mixture preferably have the Virahol/proportion of ethanol of 40: 65 (v/v).When the inventive method of preparation Type B anhydrous ondansetron hydrochloride is when at high temperature carrying out, preferred solvent is the 1-butanols, and with this mixture heating up to refluxing.
The inventive method provides following wonderful result: by with the pulp in dehydrated alcohol of A type ondansetron hydrochloride, preferably in room temperature (promptly about 20 ℃) pulp, A type ondansetron hydrochloride can be changed into the anhydrous ondansetron hydrochloride of Type B, thereby promote A type ondansetron hydrochloride simply and rapidly transforming to the anhydrous ondansetron hydrochloride of Type B.According to different parameters for example relative quantity, the temperature of particle diameter, solvent, A type ondansetron hydrochloride change into the anhydrous ondansetron hydrochloride of Type B at several hours to being up to 2 days or finishing in the longer time.Generally speaking, transform fully in room temperature and need 24-48 hour.Reaction should be carried out under drying conditions, and this is reflected under anhydrous nitrogen or the argon atmospher and carries out, perhaps via containing CaCl
2The drying tube that enough anhydrous conditions the are provided flask identical with air in carry out.
The anhydrous ondansetron hydrochloride of Type B can also make by feed HCl gas in the solution of ondansetron alkali in backflow toluene.
Prepare the anhydrous ondansetron hydrochloride of Type B by ondansetron alkali
The present invention also provides the method that is prepared the anhydrous ondansetron hydrochloride of Type B by the ondansetron free alkali.According to the inventive method, ondansetron alkali and anhydrous HCl are reacted in anhydrous organic solvent.HCl can be used as gas and provides or be dissolved in anhydrous organic solvent and for example provide in dehydrated alcohol, toluene, methyl ethyl ketone, Virahol or the ether.After reacting completely, can be by filtering to isolate the anhydrous ondansetron hydrochloride of Type B.The Type B crystal has distinctive needle-like.
Solvent (ethanol) and HCl/ ethanolic soln are that anhydrous this fact makes it possible to prepare the anhydrous ondansetron hydrochloride of Type B by the inventive method.Therefore, by this method, during reaction do not form the A type.This reaction can under refluxad be carried out at room temperature (rt).In room temperature, this reaction is a heterogenetic, and generates the anhydrous ondansetron hydrochloride of Type B with little size distribution.When under refluxad carrying out, this reaction is uniformly, and can therefore handle to obtain pure salt it with gac.Filtered while hot can obtain the Type B ondansetron hydrochloride with after removing gac by the Type B that filtrate is cooled to room temperature and go out by the filtration collecting precipitation.Can be by changing crystallization parameters, comprise that controlled chilling easily controls size distribution.
C type ondansetron hydrochloride
The invention provides a kind of new ondansetron hydrochloride form that is called C type ondansetron hydrochloride and the method for preparing C type ondansetron hydrochloride.This form is characterised in that: the strong powder x-ray diffraction peak at 6.3,24.4 ° of 2 θ angle, and at the further feature peak at following 2 θ angles: 9.2,10.2,13.1,16.9 °.The X-ray diffraction pattern of C type sample as shown in Figure 3 is provided.This form can obtain like this: after adding HCl (gas or in solution), under reflux state A type ondansetron hydrochloride is dissolved in the ethanol.After this solution cooling, filter out precipitation, and with the mother liquor reduction vaporization.The solid that is obtained by the evaporation back has produced C type ondansetron hydrochloride.C type ondansetron hydrochloride is hygroscopic, and can contain and be up to 10% water.
D type ondansetron hydrochloride
The invention provides a kind of new ondansetron hydrochloride form that is called D type ondansetron hydrochloride.This form can be used as the mixture acquisition with C type ondansetron hydrochloride.D type ondansetron hydrochloride is to obtain like this: the ratio of A type ondansetron hydrochloride with the about 1 milliliter of dimethylbenzene of every gram A type is dispersed in the dimethylbenzene, then with this dispersion more than 150 ℃, preferred temperature fusing more than 180 ℃, this melt is poured in the cold alcohol, preferably poured in the ethanol with the ratio of about 10 milliliters of ethanol/gram dispersion.Alcohol temperature can for room temperature with down to room temperature, be preferably about 10 ℃.
The feature of D type ondansetron hydrochloride is the powder x-ray diffraction peak at following 2 θ angles: 8.3,14.0,14.8,25.5 °.
E type ondansetron hydrochloride
The invention provides a kind of new ondansetron hydrochloride form that is called E type ondansetron hydrochloride and the method for preparing E type ondansetron hydrochloride.
E type ondansetron hydrochloride is characterised in that: the strong powder x-ray diffraction peak at 7.4 ° of 2 θ angle, and at the further feature peak at following 2 θ angles: 6.3,10.5,11.2,12.3,13.0,14.5,15.9,17.0,20.1,20.8,24.5,26.2,27.2 °.The X-ray diffraction pattern of E type sample as shown in Figure 4 is provided.E type ondansetron hydrochloride contains the water just like the 1.8%-2.0% that measures by Karl Fisher method.This is to be equivalent to each ondansetron hydrochloride molecule 1/3 molecular water (theoretical value: stoichiometric calculation value 1.8%) is arranged.
We are surprised to find, and handle A type ondansetron hydrochloride and can cause forming E type ondansetron hydrochloride in Virahol.Can in Virahol, under room temperature or reflux temperature, handle ondansetron hydrochloride, preferred A type dihydrate, to obtain E type ondansetron hydrochloride.
Have been found that the E type ondansetron hydrochloride that obtains by processing A type ondansetron hydrochloride in Virahol comprises the Virahol of about 8-10% or 14%.The typical TGA curve (accompanying drawing 5) of E type ondansetron hydrochloride shown in the weight loss that is up to about 120 ℃ about 2%, and in about 150 ℃ 9% or 14% rapid weight loss.According to stoichiometric calculation, E type ondansetron hydrochloride can be used as a solvate of Virahol or there be (the expection stoichiometric calculation value of Virahol half solvate is 8.4%, and the expection stoichiometric calculation value of Virahol one solvate is 15.4%) in half solvate of Virahol.Also find, be up to 60% relative humidity during one week when being exposed to, E type ondansetron hydrochloride can contain and be up to 10% moisture and can not change its crystalline structure.
H type ondansetron hydrochloride
The invention provides a kind of new ondansetron hydrochloride form that is called H type ondansetron hydrochloride and the method for preparing H type ondansetron hydrochloride.H type ondansetron hydrochloride can obtain like this: according to the inventive method, with the ondansetron alkali dissolution in ethanol, preferred dehydrated alcohol, add the ethanol/hydrogen chloride solution that presents in an amount at least sufficient to provide 1.5 equivalent HCl, be settled out H type ondansetron hydrochloride to promote crystallization (1g/86ml) by adding t-butyl methyl ether or ether (preferred anhydrous and new distillatory).Can be in the temperature more than the room temperature, preferably at the solution of about 45 ℃ of heating ondansetron alkali in dehydrated alcohol.When using ether as solvent, H type ondansetron hydrochloride can also obtain as the mixture with the anhydrous ondansetron hydrochloride of Type B.Isolating H type ondansetron hydrochloride contain 2% the water of having an appointment.
The feature of H type ondansetron hydrochloride is the unique powder x-ray diffraction peak at following 2 θ angles: 7.8,14.0,14.8,24.7, and 25.6 °.The X-ray diffraction pattern of H type sample as shown in Figure 6 is provided.
I type ondansetron hydrochloride
The invention provides a kind of new ondansetron hydrochloride form that is called I type ondansetron hydrochloride and the method for preparing I type ondansetron hydrochloride.Can in methanol vapor, A type or anhydrous ondansetron hydrochloride be handled several days-2 weeks, to generate I type ondansetron hydrochloride.In order to make most of sample change into the I type, need the time in 2 weeks.I type ondansetron hydrochloride contains just like 3.1% the water of measuring by Karl Fisher method.This is to be equivalent to each ondansetron hydrochloride molecule 1/2 molecular water (theoretical value: stoichiometric calculation value 2.5%) is arranged.I type ondansetron hydrochloride contains and is up to 10% methyl alcohol, and this and a methylate stoichiometric calculation of about 9% value are unanimous on the whole.
I type ondansetron hydrochloride is characterised in that: the strong XRD peak at 24.9 ° of 2 θ angle, and at other XRD peak at following 2 θ angles: 6.9,8.2,8.7,9.1,9.3,9.9,11.1,11.6,13.8,16.1,16.9,17.9,21.1,22.7,25.7,26.6,27.4,27.9 ± 0.2 °.X-ray diffraction pattern as shown in Figure 7 is provided.The typical heat weight analysis curve (accompanying drawing 8) of I type has shown about 10% weight loss in room temperature-Yue 130 ℃.
According to the present invention, the new ondansetron hydrochloride form of the present invention can be made into and is used in particular for treating various disease conditions, comprises prevention and cancer chemotherapy, the relevant nausea and vomiting and the pharmaceutical composition that the back is nauseating and/or vomit of performing the operation of radiotherapy.Such composition comprises the new ondansetron hydrochloride form of a kind of the present invention and pharmaceutically acceptable carrier well known by persons skilled in the art and/or vehicle.
These compositions are preferably made the medicine of oral or intravenous administration.Suitable oral administered dosage form comprises that the pill, dragee, sachet of tablet, compression or dressing, hard or gelatine capsule, hypogloeeis are with tablet, syrup and suspension.Though those skilled in the art will know that dosage will be along with factors such as indication, patient ages and become, ondansetron hydrochloride polymorphic form of the present invention and hydrate are generally with the about 32mg/ of about 8-days, the preferably about 24mg/ of about 8-days per daily dose administration.In addition, the new ondansetron hydrochloride form of the present invention can be used as every pharmaceutical preparation administration that contains the new ondansetron hydrochloride form of the about 32mg of the 4mg-that has an appointment.The new ondansetron hydrochloride form of the present invention can be preferably as every pharmaceutical preparation administration that contains the new ondansetron hydrochloride form of 4mg, 8mg or 24mg.In addition, the new ondansetron hydrochloride form of the present invention can be used as the oral liquid administration that every 5ml contains new ondansetron hydrochloride form of containing of 4mg ondansetron.
Embodiment
The powder x-ray diffraction pattern is to pass through methods known in the art, use Philips powder x-ray diffraction instrument, Phillips Generator TW1830, Goniometer modelPW3020, MPD Control PW3710, have Cu target anodic X-x ray tube, the Monochromator proportional counter obtains with 2 ° of/minute sweep velocitys.
Size distribution is according to means known in the art, by laser diffraction technology, uses to be equipped with that 50-80ml small volume pond obtains as the Malvern Laser DiffractionMastersizer S of flow cell.Use silicon fluid F-10 as thinner, be added in the 5ml thinner in the 10ml vial by sample sample is disperseed little aliquots containig.By vortex this suspension was mixed 5 seconds, supersound process was come broken hard aggregation in 2.5 minutes in open bottles then.Hanging drop is added in the flow cell that is filled with thinner until reaching required blur level (15-28%).After the recirculation 1 minute, begin to measure with the pump speed of about 1700-1800rpm.
As known in the art, experiment condition is for example ultrasonic, vortex or any other dispersion medium are meant with particles dispersed and broken owing to during drying may be present in aggregation in the material due to the particle bond, so that the size distribution of accurate primary particle to be provided.Therefore, used experiment condition can become with there being aggregation along with the outward appearance of sample.
Prepare A type ondansetron with different hydration level by the ondansetron free alkali
Embodiment 1: in room temperature with ondansetron alkali (400mg, 1.36 * 10
-3Mole) is suspended in the 40ml dehydrated alcohol.This suspension is heated to backflow with the dissolving ondansetron.Under reflux state, stir after 20 minutes, add the ethanolic soln that contains 1.1 equivalent HCl.With this reaction mixture restir 10 minutes under this temperature, be cooled to 0 ℃ then lentamente.After 1 hour,, and, obtained 90mg A type ondansetron hydrochloride 0 ℃ of stirring 50 ℃ of vacuum-dryings with the solid vacuum filtration.KF＝10％。
Embodiment 2: in room temperature with ondansetron alkali (400mg, 1.36 * 10
-3Mole) is suspended in the 12ml dehydrated alcohol.This suspension is heated to backflow with the dissolving ondansetron.Under reflux state, stir after 20 minutes, add the ethanolic soln that contains 1.1 equivalent HCl.With this reaction mixture restir 10 minutes under this temperature, be cooled to 0 ℃ then lentamente.After 1 hour,, and, obtained 536mg A type ondansetron hydrochloride 0 ℃ of stirring 50 ℃ of vacuum-dryings with the solid vacuum filtration.KF＝8.1％。
Embodiment 3: in room temperature with ondansetron alkali (400mg, 1.36 * 10
-3Mole) is suspended in 1: 1 mixture of 16ml ethanol and Virahol.This suspension is heated to backflow with the dissolving ondansetron.Under reflux state, stir after 20 minutes, add the ethanolic soln that contains 1.1 equivalent HCl.With this reaction mixture restir 10 minutes under this temperature.With solvent evaporation, obtained A type ondansetron hydrochloride dihydrate.
Embodiment 4: in room temperature with ondansetron alkali (400mg, 1.36 * 10
-3Mole) is suspended in the 40ml dehydrated alcohol.This suspension is heated to backflow with the dissolving ondansetron.Under reflux state, stir after 20 minutes, add the ethanolic soln that contains 1.5 equivalent HCl.With this reaction mixture restir 10 minutes under this temperature, be cooled to 0 ℃ then lentamente.After 1 hour,, and, obtained 320mg A type ondansetron hydrochloride 0 ℃ of stirring 50 ℃ of vacuum-dryings with the solid vacuum filtration.KF＝8.1％。
Embodiment 5: in room temperature with ondansetron alkali (400mg, 1.36 * 10
-3Mole) is suspended in the 14ml dehydrated alcohol.This suspension is heated to backflow with the dissolving ondansetron.Under reflux state, stir after 20 minutes, add the ethanolic soln that contains 1.5 equivalent HCl.With this reaction mixture restir 10 minutes under this temperature.With solvent evaporation, obtained 280mg A type ondansetron hydrochloride.KF＝9.3％。
Embodiment 6: in room temperature with ondansetron alkali (400mg, 1.36 * 10
-3Mole) is suspended in the 12ml dehydrated alcohol.The molecular sieve that in this flask, adds 4 dusts.Then this suspension is heated to backflow with the dissolving ondansetron.Under reflux state, stir after 20 minutes, add the ethanolic soln that contains 1.5 equivalent HCl.With this reaction mixture restir 10 minutes under this temperature, be cooled to 0 ℃ then lentamente.After 1 hour,, and, obtained 296mg A type ondansetron hydrochloride 0 ℃ of stirring 50 ℃ of vacuum-dryings with the solid vacuum filtration.KF＝9.5％。
Embodiment 7: in room temperature with ondansetron alkali (400mg, 1.36 * 10
-3Mole) is suspended in the 20ml dehydrated alcohol.This suspension is heated to backflow with the dissolving ondansetron.Under reflux state, stir after 20 minutes, be added in the solution that contains 1.1 equivalent HCl in the Virahol.With this reaction mixture restir 10 minutes under this temperature, be cooled to 0 ℃ then lentamente.After 1 hour,, and, obtained 290mgA type ondansetron hydrochloride 0 ℃ of stirring 50 ℃ of vacuum-dryings with the solid vacuum filtration.KF＝9.5％。
Embodiment 8: in room temperature with ondansetron alkali (2.5g, 8.5 * 10
-3Mole) is dissolved in the 80ml chloroform.Fed 1.1 equivalent HCl gases with 20 minutes in this solution of clockwise then.With this reaction mixture restir 30 minutes at room temperature.With the solid vacuum filtration, and, obtained 2.8g A type ondansetron hydrochloride 50 ℃ of vacuum-dryings.KF＝5.4％。
Embodiment 9: in room temperature with ondansetron alkali (2.5g, 8.5 * 10
-3Mole) is dissolved in the 87.5ml chloroform.Fed 1.1 equivalent HCl gases with 20 minutes in this solution of clockwise then.With this reaction mixture restir 30 minutes at room temperature.With the solid vacuum filtration, and, obtained 2.5g A type ondansetron hydrochloride 50 ℃ of vacuum-dryings.
Embodiment 10: in room temperature with ondansetron alkali (5g, 17.06 * 10
-3Mole) is dissolved in the 175ml chloroform.In this solution, fed HCl gas 15 minutes in room temperature.In this reaction mixture, add 0.6 lentamente and work as water gaging.With this reaction mixture restir 3 hours at room temperature.Then with the solid vacuum filtration, and 50 ℃ of vacuum-dryings, obtained 6.3g A type ondansetron hydrochloride.KF＝8.4％。
Embodiment 11: in room temperature with ondansetron alkali (5g, 17.06 * 10
-3Mole) is suspended in H
2O/CHCl
3(140/20v/v) in the mixture.This reaction mixture is heated to reflux temperature, adds 1.1 equivalent 1N hydrochloric acid by syringe pump with 1ml/ minute speed then.This reaction mixture stirring at room 30 minutes, is cooled to 5 ℃ then lentamente.With the partly precipitated vacuum filtration that during cooling forms come out (1.7g),, obtained white solid 50 ℃ of vacuum-dryings.Mother liquor is spent the night in the room temperature placement, obtained other a collection of precipitation (1.7g), it is filtered and vacuum-drying.These two batches of products all are A type ondansetron hydrochlorides.
Prepare A type ondansetron monohydrate by A type ondansetron hydrochloride dihydrate
Embodiment 12: A type ondansetron hydrochloride dihydrate (5g) was refluxed 22 hours in 70ml 96%EtOH heated in water solution.This reaction mixture is cooled to room temperature, is cooled to 0 ℃ then.Filter out solid precipitation,, obtained 1.2g A type ondansetron hydrochloride monohydrate, KF=5.4% 65 ℃ of dryings 20 hours.
Embodiment 13: A type ondansetron hydrochloride dihydrate (5.0g) was refluxed 22 hours in 70ml 90%EtOH heated in water solution.This reaction mixture is cooled to room temperature, is cooled to 0 ℃ then.Filter out solid,, obtained 4.0g A type ondansetron hydrochloride monohydrate, KF=5.0% 65 ℃ of dryings 20 hours.
Embodiment 14: with A type ondansetron hydrochloride dihydrate (5.0g) in the 70ml 90%EtOH aqueous solution in room temperature pulp 22 hours.Filter out solid then,, obtained 3.5g A type ondansetron hydrochloride monohydrate, KF=5.2% 65 ℃ of dryings 20 hours.
Embodiment 15: with A type ondansetron hydrochloride dihydrate (5g) in the 70ml 50%EtOH aqueous solution in room temperature pulp 22 hours.Add methyl ethyl ketone (100ml) then to be settled out ondansetron hydrochloride.This mixture is cooled to 0 ℃, filters out precipitation,, obtained 0.4g A type ondansetron hydrochloride monohydrate, KF=5.2% 65 ℃ of dryings 20 hours.
Embodiment 16: with A type ondansetron hydrochloride dihydrate (5g) in the 70ml 50%EtOH aqueous solution in room temperature pulp 22 hours.Filter out solid then,, obtained 0.4g A type ondansetron hydrochloride monohydrate, KF=5.7% 65 ℃ of dryings 20 hours.
By adding 125ml MEK causing precipitation, and vacuum filtration, from mother liquor, be recovered to a part of compound.Solid 65 ℃ of dryings 20 hours, has been obtained 1.7g A type ondansetron hydrochloride monohydrate, KF=5.4%.
Embodiment 17: with A type ondansetron hydrochloride dihydrate (5g) in the 70ml 96%EtOH aqueous solution in room temperature pulp 22 hours.Filter out solid then,, obtained 3.8g A type ondansetron hydrochloride, KF=6.1% 65 ℃ of dryings 20 hours.
Embodiment 18: with the slurries of 5g A type ondansetron hydrochloride dihydrate in EtOH/IPA (40ml/65ml) mixture with the energy supersound process of 50% amplitude, 3.5KJ 2 minutes.
Use the 8mm filter paper filtering to go out white solid then, and, obtained 2.7g A type ondansetron hydrochloride, KF=4.8% 65 ℃ of dryings 20 hours.
Embodiment 19: in the 250ml flask, add the suspension of A type ondansetron hydrochloride dihydrate (5g) in EtOH/ toluene (110ml/50ml) mixture.Give this flask fit on water distilling apparatus.Under normal pressure, distill 45 milliliters of solvent devices and obtain settled solution.With 1 hour this reaction mixture is cooled to 10 ℃ then.Vacuum filtration goes out precipitation, in 50 ℃ of dryings 16 hours, has obtained 3.7g A type ondansetron hydrochloride, KF=6.1% in vacuum drying oven.
The preparation moisture content is the A type ondansetron hydrochloride of 6-9%
Embodiment 20: with the slurries of 5g A type ondansetron hydrochloride dihydrate in the 90%EtOH aqueous solution with the energy supersound process of 50% amplitude, 3.5KJ 2 minutes.Using the aperture then is that 8 microns filter paper filtering goes out white solid, and 65 ℃ of dryings 20 hours, has obtained 2.7g A type ondansetron hydrochloride, KF=6.86%.
Embodiment 21: with the slurries of 5g A type ondansetron hydrochloride dihydrate in EtOH/IPA (65ml/40ml) mixture with the energy supersound process of 50% amplitude, 3.5KJ 2 minutes.Using the aperture then is that 8 microns filter paper filtering goes out white solid, and 65 ℃ of dryings 20 hours, has obtained 3.6g A type ondansetron hydrochloride, KF=6.7%.
Embodiment 22: the slurries of 5g A type ondansetron hydrochloride dihydrate in toluene (100ml) were heated 17 hours in 100 ℃.Then this reaction mixture is cooled to 0 ℃.Vacuum filtration goes out white precipitate, in 50 ℃ of dryings 16 hours, has obtained 4.0g A type ondansetron hydrochloride, KF=7.8% in vacuum drying oven.
Embodiment 23: with A type ondansetron hydrochloride dihydrate (5g) reflux a few hours in anhydrous EtOH/ toluene (45ml/20ml).After stirred overnight at room temperature,, in vacuum drying oven,, obtained 4.0g A type ondansetron hydrochloride, KF=7.8% in 50 ℃ of dryings 16 hours with the solid vacuum filtration.
Embodiment 24: A type ondansetron hydrochloride dihydrate (2.1g) is heated to reflux temperature in EtOH/ toluene (45ml/20ml) mixture.Under normal pressure, distill out the 25ml solvent then.With 3 hours this reaction mixture is cooled to 0 ℃.Vacuum filtration goes out white precipitate, in 50 ℃ of dryings 5 hours, has obtained 1.4g A type ondansetron hydrochloride, KF=8.8% in vacuum drying oven.
Embodiment 25: with the slurries of 5g A type ondansetron hydrochloride dihydrate in anhydrous EtOH (70ml) with the energy supersound process of 50% amplitude, 3.5KJ 2 minutes.Using the aperture then is that 3 microns filter paper filtering goes out white solid, and 65 ℃ of dryings 20 hours, has obtained 3.3gA type ondansetron hydrochloride, KF=9.3%.
The anhydrous ondansetron hydrochloride of preparation Type B
Embodiment 26: to being equipped with CaCl
2Add 5.0g A type ondansetron hydrochloride and IPA/EtOH (40/65ml) mixture in the flask of drying tube.With this mixture stirring at room 22 hours.After the filtration, the gained solid 65 ℃ of dryings 20 hours, has been obtained the anhydrous ondansetron hydrochloride of 4.0g Type B, KF=0.6%.
Embodiment 27: to being equipped with CaCl
2Add 5.0g A type ondansetron hydrochloride and anhydrous EtOH (70ml) in the flask of drying tube.With this mixture stirring at room 22 hours.After the filtration, the gained solid 65 ℃ of dryings 20 hours, has been obtained 3.7g Type B ondansetron hydrochloride, KF=0.4%.
Embodiment 28: to being equipped with condenser, thermometer and CaCl
2Add ondansetron alkali (2.0g) and 280ml toluene in the three-necked flask of pipe.This mixture heating up is refluxed until obtaining settled solution.Feeding HCl gas is 1 until pH.This reaction mixture was refluxed 1 hour again, be cooled to room temperature then.Filter out the precipitation that is obtained,, obtained 1.7g Type B ondansetron hydrochloride, KF=1.6% 65 ℃ of dryings 20 hours.
Embodiment 29: with ondansetron alkali (2.0g, 6.8 * 10
-3Mol) suspension was dissolved until it in 30 minutes fully in MEK (220ml).In this solution, feed HCl gas until reaching pH=1.This reaction mixture was refluxed 1 hour again, be cooled to room temperature, vacuum filtration was 65 ℃ of dryings 20 hours.Use CaCl
2The pipe, with the gained white solid in dehydrated alcohol (70ml) in room temperature pulp 22 hours.Then with this reaction mixture vacuum filtration,, obtained the anhydrous ondansetron hydrochloride of 1.9g Type B 65 ℃ of dryings 20 hours.
Embodiment 30: with ondansetron alkali (3g, 10.2 * 10
-3Mol) suspension was dissolved until it in 15 minutes fully in MEK (330ml).Add HCl ethanolic soln (1.5 equivalent).This reaction mixture was refluxed 30 minutes again, be cooled to room temperature, vacuum filtration was 65 ℃ of dryings 20 hours.Use CaCl then
2The pipe, with the gained white solid in the anhydrous EtOH/IPA of 105ml (65/40ml) mixture in room temperature pulp 22 hours.With this reaction mixture vacuum filtration,, obtained the anhydrous ondansetron hydrochloride of 3.16g Type B 65 ℃ of dryings 20 hours.
Embodiment 31: with ondansetron alkali (5g) (17.0 * 10
-3Mol) be suspended among the anhydrous EtOH of 250ml.Add HCl ethanolic soln (1.5 equivalent) then.With this reaction mixture warm (45 ℃) to obtain settled solution.Allow this reaction mixture be cooled to room temperature, add anhydrous diethyl ether (430ml) then to be settled out solid.Vacuum filtration goes out precipitation, in 65 ℃ of dryings 24 hours, has obtained the anhydrous ondansetron hydrochloride of 3.16g Type B in baking oven.KF＝1.7％。
Embodiment 32: with ondansetron alkali (5g) (17.0 * 10
-3Mol) be suspended in the 250ml dehydrated alcohol.Add HCl ethanolic soln (1.5 equivalent) then.Described ethanolic soln makes by feed HCl gas in dehydrated alcohol under anhydrous condition.With this reaction mixture warm (45 ℃) obtaining settled solution, and with this solution filtered while hot.In filtrate, add anhydrous diethyl ether (430ml) to be settled out solid in room temperature.Vacuum filtration goes out precipitation, in 65 ℃ of dryings 18 hours, has obtained the anhydrous ondansetron hydrochloride of 3.16g Type B in baking oven.KF＝1.0％。
Preparation C type ondansetron hydrochloride
Embodiment 33: under reflux temperature with ondansetron alkali (1.5g, 5.11 * 10
-3Mol) be dissolved in the new distillatory dehydrated alcohol (150ml).Under refluxad add HCl ethanolic soln (1.1 equivalent) then.This reaction mixture was stirred 20 minutes, and be cooled to room temperature lentamente.Very dense precipitation has appearred in room temperature.With this mixture vacuum filtration, obtained the 536mg white solid then.With ethanol phase reduction vaporization, obtained 824mg C type ondansetron hydrochloride.KF＝9.9％。
Embodiment 34: with ondansetron alkali (5g) (17.0 * 10
-3Mol) be suspended in the new distillatory dehydrated alcohol (150ml) with 10g 4 molecular sieves.This reaction mixture is dissolved until raw material fully 80 ℃ of heating.Drip HCl ethanolic soln (1.5 equivalent) in room temperature, and this reaction mixture was stirred 15 minutes.This mixture is cooled to room temperature lentamente, is cooled to 0 ℃ then so that precipitation is complete.With this solid mixture vacuum filtration, with IPA washing 3 times (3 * 10ml), obtained the 3.07g white solid.Ethanol is spent the night 4 ℃ of placements, and filtration under diminished pressure goes out precipitation, has obtained the 600mg solid.With the mother liquor reduction vaporization of this part, obtained 1g C type ondansetron hydrochloride then.KF＝9.9％。
Preparation D type ondansetron hydrochloride
Embodiment 35: with A type ondansetron hydrochloride (5g) (17.0 * 10
-3Mol) be suspended in the dimethylbenzene (5ml).This suspension is melted until ondansetron hydrochloride in the heating of the temperature more than 180 ℃.Then this melt is poured lentamente into temperature in-10 ℃ the anhydrous EtOH solution (50ml).The gained solid was stirred gravity filtration then 30 minutes in-10 ℃ in anhydrous EtOH.With solid in baking oven in 65 ℃ of dryings 18 hours, obtained 1.31g D type ondansetron hydrochloride.KF＝3.84％。
Preparation E type ondansetron hydrochloride
Embodiment 36: with A type ondansetron hydrochloride (5g, 13.6 * 10
3Mol) in IPA (70ml), spend the night in the room temperature pulp.Vacuum filtration goes out white solid then, in 65 ℃ of dryings 24 hours, has obtained 4.9g E type ondansetron hydrochloride in baking oven, is white solid.KF＝1.8％。
Embodiment 37: with A type ondansetron hydrochloride (5g, 13.6 * 10
-3Mol) in IPA (40ml) under reflux temperature pulp spend the night.Vacuum filtration goes out white solid, in 65 ℃ of dryings 24 hours, has obtained 5g E type ondansetron hydrochloride in baking oven, is white solid.KF＝2.1％。
Preparation H type ondansetron hydrochloride
Embodiment 38: with ondansetron alkali (5g) (17.0 * 10
-3Mol) be suspended among the anhydrous EtOH of 250ml.Add HCl ethanolic soln (1.5 equivalent) then.With this reaction mixture warm (45 ℃) until obtaining settled solution, and with this settled solution filtered while hot.In this filtrate, add t-butyl methyl ether (200ml) and go out solid with sedimentation.Vacuum filtration goes out precipitation, in 65 ℃ of dryings 24 hours, has obtained the anhydrous ondansetron hydrochloride of 0.4g H type in baking oven.KF＝1.7％。
Preparation I type ondansetron hydrochloride
Embodiment 39: I type ondansetron hydrochloride is by making hydration or anhydrous ondansetron hydrochloride in methanol vapor in 3 weeks of room temperature treatment.Step is as follows: 100-200mg A type ondansetron hydrochloride sample or anhydrous ondansetron hydrochloride sample are kept in the 10ml open glass bottle.This open bottles is placed in the bigger bottle that contains several ml methanol.The bottle sealing that this is bigger is to produce saturated atmosphere.After 2 weeks, be not for further processing, analyze the gained solid, found that it is I type ondansetron hydrochloride by X-ray diffraction.
Prepare the anhydrous ondansetron of Type B by ondansetron alkali
Embodiment 40: ondansetron alkali (10g, 34.1mmol, 1 equivalent), 250ml dehydrated alcohol and 8.4ml 23.3%HCl ethanolic soln (51.2mmol, 1.5 equivalents) are added in the 500ml round-bottomed flask that is equipped with calcium chloride tube and mechanical stirrer.With this mixture stirring at room 66 hours.Filter out solid then, with absolute ethanol washing (2 * 20ml), and, obtained 8.7g (77%) Type B ondansetron hydrochloride, KF=0.66% 65 ℃ of dryings 20 hours.
Embodiment 41: ondansetron alkali (10g, 34.1mmol, 1 equivalent), 250ml dehydrated alcohol and 8.4ml 23.3%HCl ethanolic soln (51.2mmol, 1.5 equivalents) are added in the 500ml round-bottomed flask that is equipped with calcium chloride tube, mechanical stirrer and condenser.This mixture heating up is refluxed to obtain settled solution, refluxed about 30 minutes.Then this reaction mixture is cooled to room temperature, during formed precipitation.With this reaction mixture restir 45 hours.Filter out solid then, with absolute ethanol washing (2 * 20ml), and, obtained 8.5g (76%) Type B ondansetron hydrochloride, KF=0.34% 65 ℃ of dryings 20 hours.
Claims (93)
1. ondansetron hydrochloride monohydrate.
2. the ondansetron hydrochloride monohydrate that contains 5% moisture of having an appointment.
3. the ondansetron hydrochloride monohydrate of claim 1, it is characterized in that: its powder x-ray diffraction pattern has a strong peak at 23.3 ± 2 ° of 2 θ angle.
4. the ondansetron hydrochloride monohydrate of claim 3, its feature also is: its powder x-ray diffraction pattern has the peak at following 2 θ angles: 6.1,12.4,17.0,18.3,19.2,20.3,20.9,24.1,25.8,28.1 and 30.3 ± 0.2 °.
5. the method for ondansetron hydrochloride monohydrate of preparation claim 1, comprising the following step:
A) the ondansetron hydrochloride dihydrochloride dihydrate crystal is contacted with the mixture of water in ethanol of about 4%-about 50%,
B) separating alcohol: water mixture and
C) collection is as the crystal of ondansetron hydrochloride monohydrate.
6. the method for claim 5, wherein said contact is at ethanol: carry out under the reflux temperature of water mixture.
7. the method for claim 5, wherein said dihydrate is represented the A type that its crystalline structure is identical with the monohydrate called after.
8. the method for preparing A type ondansetron hydrochloride dihydrate, comprising the following step:
A) provide the ondansetron hydrochloride monohydrate crystal of claim 1,
B) under the atmosphere of 50% relative humidity or bigger relative humidity with described crystal hydration and
C) collect the hydrate crystal that contains 10% crystal water of having an appointment.
9. the A type ondansetron hydrochloride that contains the 5%-10% moisture of having an appointment.
10. the method for A type ondansetron hydrochloride of preparation claim 9, comprising the following step:
A) the ondansetron free alkali is suspended in is selected from the following liquid medium: the mixture of dehydrated alcohol, ethanol and Virahol and chloroform,
B) make the free alkali dissolving by in suspension, adding anhydrous HCl,
C) from liquid medium crystallization go out ondansetron hydrochloride and
D) crystal is separated from liquid medium.
11. the method for claim 10, wherein said liquid medium is a dehydrated alcohol.
12. the method for claim 10, wherein with respect to the ondansetron free alkali, HCl adds with 1 ± 0.1 equivalent.
13. the method for claim 10, wherein anhydrous HCl adds as gas.
14. the method for claim 10, wherein anhydrous HCl adds as the solution in inert organic solvents.
15. the method for claim 10 is wherein with the dissolving of described dehydrated alcohol heating with promotion ondansetron free alkali.
16. the method for A type ondansetron hydrochloride of preparation claim 9, comprising the following step:
A) by be selected from following liquid medium and contact the ondansetron hydrochloride dihydrate is dewatered: the mixture of the mixture of ethanol, ethanol and water, toluene and ethanol and toluene,
B) with liquid medium and crystal separation is opened and
C) collect crystal.
17. the method for claim 16, wherein during dewatering with the crystal mechanical stirring.
18. the method for claim 17, wherein said mechanical stirring is a supersound process.
19. anhydrous ondansetron hydrochloride.
20.B the anhydrous ondansetron hydrochloride of type.
21.B the type ondansetron hydrochloride is characterized in that: its powder x-ray diffraction pattern has the peak at following 2 θ angles: 10.5,11.9,13.0,13.5 and 15.1 ± 0.2 °.
22.B the type ondansetron hydrochloride is characterized in that: its powder x-ray diffraction pattern has the peak at following 2 θ angles: 10.5,11.9,10.5,13.0,13.5,15.1,20.9,22.7, and 24.0 and 25.7 ± 0.2 °.
23. pharmaceutical composition wherein comprises each ondansetron hydrochloride and pharmaceutically acceptable carrier of claim 1-22.
24. the method for and/or vomiting nauseating with the medicine composite for curing of claim 23.
25. prepare each the method for ondansetron hydrochloride of claim 19-22 by handle ondansetron hydrochloride with absolute alcohol.
26. the method for claim 25, wherein said solvent is a dehydrated alcohol.
27. the method for claim 25, wherein the ondansetron hydrochloride of handling with absolute alcohol is the A type.
28. the method for claim 25, wherein said processing is carried out at about 20 ℃.
29. the method for claim 28, wherein the ondansetron hydrochloride of handling with absolute alcohol is the A type.
30. the method for claim 25, wherein said alcohol are ethanol, Virahol, 1-butanols or its mixture.
31. the method for claim 30, wherein the ondansetron hydrochloride of handling with absolute alcohol is the A type.
32. prepare each the method for ondansetron hydrochloride of claim 19-22 by in anhydrous organic solvent, handling ondansetron hydrochloride.
33. the method for claim 32, wherein said solvent is a dehydrated alcohol.
34. the method for claim 32, wherein the ondansetron hydrochloride of handling with absolute alcohol is the A type.
35. the method for claim 32, wherein said solvent is a ketone.
36. the method for claim 35, wherein the ondansetron hydrochloride of handling with absolute alcohol is the A type.
37. the method for claim 32, wherein said processing is carried out at about 20 ℃.
38. the method for claim 37, wherein the ondansetron hydrochloride of handling with absolute alcohol is the A type.
39. have Type B ondansetron hydrochloride less than about 300 microns particle diameter.
40. pharmaceutical composition wherein comprises Type B ondansetron hydrochloride and pharmaceutically acceptable carrier of claim 39.
41. have Type B ondansetron hydrochloride less than about 200 microns particle diameter.
42. pharmaceutical composition wherein comprises Type B ondansetron hydrochloride and pharmaceutically acceptable carrier of claim 41.
43. have Type B ondansetron hydrochloride less than about 40 microns particle diameter.
44. pharmaceutical composition wherein comprises Type B ondansetron hydrochloride and pharmaceutically acceptable carrier of claim 43.
45. moisture content is up to about 2% the anhydrous ondansetron hydrochloride of Type B.
46. prepare the method for Type B ondansetron hydrochloride, comprise toluene solution reaction with HCl gas and ondansetron alkali.
47. the method for claim 46 is wherein dissolved ondansetron hydrochloride under the reflux temperature of toluene.
48. the method for claim 46 wherein is passed into hydrogen chloride gas in the toluene solution of ondansetron.
49.C type ondansetron hydrochloride and hydrate thereof is characterized in that: the powder x-ray diffraction peak at 6.3 and 24.4 ± 0.2 ° of 2 θ angle, and at other peak at following 2 θ angles: 9.2,10.2,13.1 and 16.9 ± 0.2 °.
50.C type ondansetron hydrochloride and hydrate thereof is characterized in that: powder x-ray diffraction peak at following 2 θ angles: 6.3,9.2,10.2,13.1,16.9 and 24.4 ± 0.2 °.
51. the method for preparation claim 49 or 50 product, comprising the following step:
A) with the ondansetron alkali dissolution in ethanol,
B) ethanolic soln of adding hydrogenchloride,
C) filter and
D) with mother liquid evaporation.
52.D type ondansetron hydrochloride and hydrate thereof is characterized in that: powder x-ray diffraction peak: 8.3,14.0,14.8 and 25.5 ± 0.2 ° at following 2 θ angles.
53. the preparation D type ondansetron hydrochloride of claim 52 and the method for hydrate thereof, comprising the following step:
A) in the presence of dimethylbenzene, ondansetron hydrochloride is melted; With
B) this melt is added in the ethanol.
54. the method for claim 53 wherein melts A type ondansetron hydrochloride in the presence of dimethylbenzene.
55. the method for claim 53, wherein the alcoholic acid temperature is about 15 ℃-Yue room temperature.
56. the method for claim 55, wherein the alcoholic acid temperature is about 10 ℃.
57.E type ondansetron hydrochloride and hydrate thereof is characterized in that: the strong powder x-ray diffraction peak at 7.4 ° of 2 θ angle, and at the further feature peak at following 2 θ angles: 6.3,10.5,11.2,12.3,13.0,14.5,15.9,20.1,20.8,24.5,26.2 and 27.2 ± 0.2 °.
58.E type ondansetron hydrochloride and hydrate thereof is characterized in that: the strong powder x-ray diffraction peak at 7.4 ° of 2 θ angle, and at the further feature peak at following 2 θ angles: 6.3,10.5,11.2,12.3,13.0,14.5,15.9,20.1,20.8,24.5,26.2 and 27.2 ± 0.2 °.
59. the method for the product of preparation claim 57 or 58 is comprising the step of handling ondansetron hydrochloride in Virahol.
60. the method for claim 59, wherein said ondansetron hydrochloride are the A types.
61. the method for claim 59, wherein the temperature of Virahol is about room temperature-Yue reflux temperature.
62. ondansetron hydrochloride Virahol thing.
63.E type ondansetron hydrochloride Virahol thing.
64.E type ondansetron hydrochloride one Virahol thing.
65.E type ondansetron hydrochloride half Virahol thing.
66. moisture content is up to about 10% E type ondansetron hydrochloride.
67.H type ondansetron hydrochloride and hydrate thereof is characterized in that: powder x-ray diffraction peak: 7.8,14.0,14.8,24.7 and 25.6 ± 0.2 ° at following 2 θ angles.
68. the method for H type ondansetron hydrochloride of preparation claim 67, comprising the following step:
A) ondansetron alkali is suspended in the dehydrated alcohol;
B) ethanolic soln of adding hydrochloric acid;
C) add ether to cause precipitation; With
D) isolate product.
69. the method for claim 68, wherein said ether are methyl tertiary butyl ether or ether.
70. the method for claim 68, wherein said ether is anhydrous.
71. pharmaceutical composition wherein comprises claim 49,50,52,57,58 and each ondansetron hydrochloride and pharmaceutically acceptable carrier of 62-67.
72. ondansetron hydrochloride methylate.
73.I type ondansetron hydrochloride methylate.
74.I type ondansetron hydrochloride and hydrate thereof is characterized in that: the strong XRD peak at 25.0 ± 0.2 ° of 2 θ angle, and at other XRD peak at following 2 θ angles: 8.2,9.3,9.9,11.1 and 24.9 ± 0.2 °.
75.I type ondansetron hydrochloride and hydrate thereof is characterized in that: the strong XRD peak at 25.0 ± 0.2 ° of 2 θ angle, and at other XRD peak at following 2 θ angles: 8.2,9.3,9.9,11.1,13.9,16.0,17.0,21.0,22.6,25.8,27.3 and 28.0 ± 0.2 °.
76.I type ondansetron hydrochloride and hydrate thereof is characterized in that: the strong XRD peak at 25.0 ± 0.2 ° of 2 θ angle, and at other XRD peak at following 2 θ angles: 6.9,8.2,8.7,9.1,9.3,9.9,11.1,11.6,13.8,16.1,16.9,17.9,21.1,22.7,25.7,26.6,27.4 and 27.9 ± 0.2 °.
77. the method for crystallization I type ondansetron hydrochloride comprises ondansetron hydrochloride is exposed under the methanol vapor.
78. the method for claim 77, wherein said exposure are to carry out about 3 weeks or shorter time.
79. the method for claim 77, wherein said exposure is carried out in room temperature.
80. the method for claim 77 wherein is that A type ondansetron hydrochloride is exposed under the methanol vapor.
81. the method for claim 77 wherein is that the Type B ondansetron hydrochloride is exposed under the methanol vapor.
82. prepare the method for the anhydrous ondansetron hydrochloride of Type B, comprising the following step:
A) with the ondansetron alkali dissolution in dehydrated alcohol;
B) add ethanol/hydrochloric acid soln; With
C) filter.
83. the method for claim 82, wherein ethanol is anhydrous basically.
84. the method for claim 82, wherein with ondansetron alkali and ethanol/hydrochloric acid soln in mixed at room temperature.
85. the method for claim 82, wherein with the mixture heating up of ondansetron alkali to reflux temperature.
86. the method for claim 82 is wherein with ondansetron alkali and ethanol/hydrochloric acid soln at the about 30-of mixed at room temperature about 70 hours.
87. being 100% particle diameter, size distribution is lower than about 100 microns ondansetron hydrochloride.
88. being 100% particle diameter, size distribution is lower than about 50 microns ondansetron hydrochloride.
89. pharmaceutical composition wherein comprises size distribution and is 100% particle diameter and is lower than about 200 microns ondansetron and pharmaceutically acceptable carrier.
90. pharmaceutical composition wherein comprises size distribution and is 100% particle diameter and is lower than about 100 microns ondansetron and pharmaceutically acceptable carrier.
91. pharmaceutical composition wherein comprises size distribution and is 100% particle diameter and is lower than about 50 microns ondansetron and pharmaceutically acceptable carrier.
92. treatment is felt sick and/or the method for vomiting, comprises the step of pharmaceutical composition of claim 91 for the treatment of patient's administering therapeutic significant quantity of this treatment to needs.
93. pharmaceutical composition wherein comprises I type ondansetron hydrochloride and pharmaceutically acceptable carrier.
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| EP1499623B1 (en) | 2002-04-29 | 2007-06-13 | TEVA Gyógyszergyár Zártkörüen Müködö Részvénytársaság | Process for preparing 1,2,3,9-tetrahydro-9-methyl-3-¬(2-methyl-1h-imidazol-1-yl)methyl|-4h-carbazol-4-one |
| FI6164U1 (en) * | 2003-01-09 | 2004-03-15 | Synthon Bv | Ondansetronformer |
| WO2006046253A1 (en) * | 2004-10-26 | 2006-05-04 | Ipca Laboratories Limited | A one-pot process for the preparation of antiemetic agent, 1,2,3,9-tetrahydro-9-methyl-3[(2-methyl)-1h-imidazole-1-yl)methyl]-4h-carbazol-4-o |
| BRPI0707324A2 (en) * | 2006-01-27 | 2011-05-03 | Eurand Inc | drug delivery systems comprising poorly basic selective 5-ht3 serotonin blocking agent and organic acids |
| NZ569984A (en) * | 2006-01-27 | 2011-06-30 | Eurand Inc | Drug delivery systems comprising weakly basic drugs and organic acids |
| US20100105724A1 (en) * | 2006-12-07 | 2010-04-29 | Helsinn Healthcare Sa | Crystalline and amorphous forms of palonosetron hydrochloride |
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|---|---|---|---|---|
| US4695578A (en) * | 1984-01-25 | 1987-09-22 | Glaxo Group Limited | 1,2,3,9-tetrahydro-3-imidazol-1-ylmethyl-4H-carbazol-4-ones, composition containing them, and method of using them to treat neuronal 5HT function disturbances |
| DE201165T1 (en) * | 1985-03-14 | 1989-04-20 | Beecham Group P.L.C., Brentford, Gb | MEDICINES FOR TREATING EMESIS, ANXIETAS AND "IRRITABLE BOWEL SYNDROME". |
| GB8518741D0 (en) * | 1985-07-24 | 1985-08-29 | Glaxo Group Ltd | Process |
| GB8518742D0 (en) * | 1985-07-24 | 1985-08-29 | Glaxo Group Ltd | Process |
| GB8630071D0 (en) * | 1986-12-17 | 1987-01-28 | Glaxo Group Ltd | Medicaments |
| GB8816187D0 (en) * | 1988-07-07 | 1988-08-10 | Glaxo Group Ltd | Medicaments |
| US5344658A (en) * | 1989-06-28 | 1994-09-06 | Glaxo Group Limited | Process and composition using ondansetron |
| EP1022025A3 (en) * | 1991-06-26 | 2002-06-05 | Sepracor, Inc. | Method and compositions for treating emesis nausea and other disorders using optically pure R(+) ondansetron |
| CA2106642C (en) * | 1992-10-14 | 2005-08-16 | Peter Bod | Carbazolone derivatives and process for preparing the same |
| GB9423511D0 (en) * | 1994-11-22 | 1995-01-11 | Glaxo Wellcome Inc | Compositions |
| GB9423588D0 (en) * | 1994-11-22 | 1995-01-11 | Glaxo Wellcome Inc | Compositions |
| CN1045437C (en) * | 1994-12-29 | 1999-10-06 | 中国科学院上海有机化学研究所 | Anthratancitone and its physiological saline synthesis |
| EP1207160A1 (en) * | 2000-11-20 | 2002-05-22 | Hanmi Pharm. Co., Ltd. | Process for the preparation of 1,2,3,9-tetrahydro-9-methyl-3-((2-methyl-1H-imidazol-1-yl)-methyl)-4H-carbazol-4-one |
| EP1499623B1 (en) * | 2002-04-29 | 2007-06-13 | TEVA Gyógyszergyár Zártkörüen Müködö Részvénytársaság | Process for preparing 1,2,3,9-tetrahydro-9-methyl-3-¬(2-methyl-1h-imidazol-1-yl)methyl|-4h-carbazol-4-one |
| JP2005529908A (en) * | 2002-04-30 | 2005-10-06 | テバ ジョジセルジャール レースベニュタールシャシャーグ | Novel crystalline form of ondansetron, process for producing the same, pharmaceutical composition containing the novel form, and method of treating nausea using the composition |
-
2001
- 2001-10-30 YU YU32003A patent/YU32003A/en unknown
- 2001-10-30 ES ES01991193T patent/ES2204358T1/en active Pending
- 2001-10-30 AU AU2002230935A patent/AU2002230935A1/en not_active Abandoned
- 2001-10-30 EP EP01991193A patent/EP1339707A2/en not_active Withdrawn
- 2001-10-30 SK SK618-2003A patent/SK6182003A3/en not_active Application Discontinuation
- 2001-10-30 KR KR10-2003-7005876A patent/KR20030042038A/en not_active Application Discontinuation
- 2001-10-30 DE DE0001339707T patent/DE01991193T1/en active Pending
- 2001-10-30 WO PCT/US2001/048720 patent/WO2002036558A2/en not_active Application Discontinuation
- 2001-10-30 PL PL01366150A patent/PL366150A1/en unknown
- 2001-10-30 US US10/016,752 patent/US20020107275A1/en not_active Abandoned
- 2001-10-30 CA CA002426026A patent/CA2426026A1/en not_active Abandoned
- 2001-10-30 HU HU0401239A patent/HUP0401239A2/en unknown
- 2001-10-30 CZ CZ20031397A patent/CZ20031397A3/en unknown
- 2001-10-30 CN CNA018183859A patent/CN1498216A/en active Pending
- 2001-10-30 IL IL15564401A patent/IL155644A0/en unknown
- 2001-10-30 JP JP2002539318A patent/JP2004525083A/en active Pending
- 2001-10-30 MX MXPA03003761A patent/MXPA03003761A/en unknown
-
2003
- 2003-04-29 IS IS6797A patent/IS6797A/en unknown
- 2003-04-29 NO NO20031928A patent/NO20031928L/en not_active Application Discontinuation
- 2003-05-28 HR HR20030432A patent/HRP20030432A2/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| HRP20030432A2 (en) | 2004-06-30 |
| MXPA03003761A (en) | 2003-07-28 |
| JP2004525083A (en) | 2004-08-19 |
| DE01991193T1 (en) | 2004-07-08 |
| SK6182003A3 (en) | 2004-03-02 |
| NO20031928D0 (en) | 2003-04-29 |
| WO2002036558A2 (en) | 2002-05-10 |
| NO20031928L (en) | 2003-06-27 |
| YU32003A (en) | 2006-05-25 |
| ES2204358T1 (en) | 2004-05-01 |
| HUP0401239A2 (en) | 2004-12-28 |
| CA2426026A1 (en) | 2002-05-10 |
| EP1339707A2 (en) | 2003-09-03 |
| KR20030042038A (en) | 2003-05-27 |
| PL366150A1 (en) | 2005-01-24 |
| IL155644A0 (en) | 2003-11-23 |
| US20020107275A1 (en) | 2002-08-08 |
| IS6797A (en) | 2003-04-29 |
| WO2002036558A3 (en) | 2003-02-06 |
| CZ20031397A3 (en) | 2003-11-12 |
| AU2002230935A1 (en) | 2002-05-15 |
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